Pharmacokinetics of the CYP 3A substrate simvastatin following administration of delayed versus immediate release oral dosage forms.

Article Details

Citation

Tubic-Grozdanis M, Hilfinger JM, Amidon GL, Kim JS, Kijek P, Staubach P, Langguth P

Pharmacokinetics of the CYP 3A substrate simvastatin following administration of delayed versus immediate release oral dosage forms.

Pharm Res. 2008 Jul;25(7):1591-600. doi: 10.1007/s11095-007-9519-6. Epub 2008 Jan 24.

PubMed ID
18213452 [ View in PubMed
]
Abstract

PURPOSE: The study was designed to evaluate the effect of delayed release (DR) on absorption and bioavailability of intestinally metabolized drugs after oral dosing, using the HMG-CoA reductase inhibitor simvastatin, a CYP3A substrate, as a model drug. MATERIALS AND METHODS: To target drug release and to assess regional gastrointestinal absorption of the CYP 3A substrate simvastatin from the distal parts of the intestine, delayed release film coated tableted oral dosage forms were developed. Simvastatin delayed release tablet, simvastatin immediate release capsule and simvastatin immediate release tablet Zocor were administered as single doses (20 mg) to fasting healthy volunteers in a crossover design. RESULTS: Simvastatin bioavailability was increased by a factor of three, as compared to the reference formulation Zocor. The overall metabolite levels from the immediate release capsules tended to be higher throughout the period studied than the metabolite levels following administration of Zocor and simvastatin delayed release dosage form. CONCLUSIONS: The interplay between gastrointestinal physiology (lower CYP 3A expression in the distal ileum and the colon) and formulation design (zero-order controlled release after a predetermined lag-time) resulted in successful absorption and bioavailability improvement and represent a viable strategy to reduce the dose of CYP 3A drugs.

DrugBank Data that Cites this Article

Drugs
Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
SimvastatinCytochrome P450 2C9ProteinHumans
Unknown
Inhibitor
Details
SimvastatinCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
SimvastatinCytochrome P450 3A5ProteinHumans
Unknown
Substrate
Details